The hepatic lipotoxicity specifically associated with HIV protease inhibitors (PIs), the core component of highly active anti-retroviral therapy (HAART), has become a major concern in the clinic, especially in patients who consume alcohol. Alcohol abuse, which alone also produces liver toxicity, is one of the most important co-morbid risk factors for liver injury in HIV patient under current therapy. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV patients, the mechanism by which alcohol exacerbates HIV PI-induced hepatic lipotoxicity has not been identified. The goal of this proposal is to examine the potential impact of alcohol use/abuse on HIV PI- induced hepatic lipotoxicity and further elucidate the underlying cellular/molecular mechanisms. The central hypothesis of this study is that alcohol and HIV PIs additively induce hepatic lipotoxicity by activating the ER stress, subsequently disrupting lipid homeostasis and inducing apoptosis in hepatocytes. In this study, we will (1) determine the impact of alcohol on HIV PI-induced activation of ER stress, (2) determine the role of ER stress in alcohol and HIV PI-induced hepatic lipotoxicity and (3) identify the mechanism by which alcohol promotes HIV PI-induced ER stress and hepatic lipotoxicity. The long-term goal of this research is to understand the molecular/cellular mechanisms by which alcohol and HAART induce hepatic lipotoxicity. The burden of liver injury in HIV patients is expected to increase as the number of patients living wit HIV continues to rise. Understanding the mechanism by which alcohol and HIV PIs induce hepatotoxicity is of great clinical importance. Completion of these objectives will help identify new cellular mechanisms of alcohol and HIV PI-induced hepatic lipotoxicity, thereby enhancing our understanding of the mechanisms of HAART-associated liver diseases and providing novel information for the future development of new preventative and therapeutic strategies.